Acute hepatitis B virus (HBV) infection is generally self-limited. However, patients remaining chronically infected are at risk for chronic liver inflammation, cirrhosis and liver carcinoma; also, they are a major source of contamination to others. Only a minority of these patients is cured by antiviral therapy. Therapeutic vaccination is needed for such patients. Chronic HBV infection correlates with poor immune responsiveness to viral antigens. Such immune tolerance is not due to emergence of mutant viruses or disappearance of effector T cells. Rather, immune response to HBV is misdirected and inefficient. Establishing a strong immune response to HBV could help to induce remission even cure the disease. Strong T cell responses are essential to clear the virus. DNA vaccines efficiently induce T cell immunity. Electroporation is becoming a method of choice for DNA vaccine delivery, by providing consistent, reproducible, high level, immunogen expression, and inducing vigorous, high magnitude immune responses. In these studies, therapeutic potential of electroporation-based DNA immunization against HBV will be tested in normal mice. End points will include rapidity, magnitude, duration, multispecificity, polyclonality and distribution of the response. Protocols matching predefined criteria will be tested in Phase II in animal models of chronic HBV infection.